Mast Cell Activation And Histamine Intolerance
Mast cells are an immune cell in the bodies immune system. They are a type of white blood cell that originates from the bone marrow and are present in most tissues of the body. They are found in connective tissue all through the body, especially under the skin, near blood vessels and lymph vessels, in nerves, and in the lungs and intestines. You find them in the largest amounts in tissues that are associated with the outside world.
Mast cells help control types of immune system responses and help repair tissues. Their primary job is to coordinate how the immune system and the nervous system respond to infections and toxins.
Mast Cells Make Lots Of Signalling Molecules
Mast cells help control types of immune system responses and help repair tissues. They release numerous signalling chemicals, also called mast cell mediators into the body as part of the immune system response against a wide range of threast such as infections and toxins. They aso release chemicals that are necessary for other types of bodily activities. These chemicals include inflammatory mediators, lysosomal enzymes, histamine, heparin, cytokines, chemokines, prostanoides, leukotrienes and proteases as well as chemicals involved in things such as bone growth and remodeling including growth factors and chondroitin sulfate. They release many of these chemicals during certain immune responses and allergic reactions. These chemicals have effects, that include both innate and adaptive immune responses, the widening of blood vessels and creation of new blood vessels, as well as venom detoxification. Although, they are a necessary part of body function they are also responsible for promoting inflammatory and allergic reactions during this process and especially if they are over stimulated or in excess amounts.
Histamine is the signaling molecule that we will be examining today. It is released in large amounts and when in too high of levels can cause an amazing amount of symptoms that can be confusing as they come and go. The symptoms tend to wax and wane like the moon. Often an individual is repetatively finding what they think is the cause only to decide it is something else. The changing symptoms make it hard for practitioners to figure out what is going on also.
Histamine is not all bad as it is needed as a neurotransmitter and it makes stomach acid and is important to the immune system when it is not in excess. So dysregulatioin is the issue. Histamine itself is not a bad guy.
Mast Cell Activation and High Histamine
Many symptoms are caused by mast cell actiation, but the most common would be reacting to a food or drink within 15 minutes after eating it. If immediately after eating or drinking something the person's skin flushes and they start to sweat, their heart races, get itchy, hives appear on the skin, they feel anxious, have abdominal pain and get diarrhea, then they should ask their Doc to consider Mast Cell Activation Disorder. Mast cells release 200 or more chemicals that can cause reactions.
Although many of these responses are acute and quick histamine is also involved in delayed hypersensitivity reactions. The reaction can depend on multiple factors including the route of exposure (local versus systemic), sites of exposure ( inhaled versus cutaneous), the dose of allergen/toxin, and the degree of previous sensitization to the allergen/toxin.
Mast cell activation always causes high histamine, but histamine can be incrased without mast cell activation.
Many of these symptoms below are due to high histamine and can be due to factors other than mast cell activation as described more below.
I would also add that histamine is a biogenic amine. There are other biogenic amines that can cause similar issues.
Symptoms usually come on quickly and are largely related to histmine. Keep that in mind.
- Itching of the skin
- Swelling of the skin
- Easy flushing or reddening of the skin
- Patchy red rashes
- Red bumps on the surface of the skin that itch
- Loss of color
- Tenderness, Pain
- Dermatographism - skin writing, where you either turn red easily or get a hive-like raised skin with a light skin scratch.
- Overreact to bee stings, mosquito bites and many medications
- Keloids have been found to have increased levels of mast cells and histamine and heparin are theorized to be involved
- Hot flushes
Head, Brain, Mind and Nervous System
- Poor memory
- Poor concentration
- Difficulty finding words
- Brain fog or disorientation following exposure to an allergen or toxin
- Increased sensitivity to lights, sound, noises, heat, cold, vibration.
- Headaches, migraines, cluster headaches, seizures, tremors, tics, paresthesias, dysautonomia (uncontrollable, spasmodic twisting motions)
- Anxiety, panic attacks, mood swings, depression, obsessive compulsive disorder, attention deficit hyperactivity disorder
- Increased chemical sensitivities and EMF sensitivity
- General cognitive dysfunction
- Thermal dysregulation
- Reduced motor control
- Ringing in the ears
- Numbness, tingling - especially hands and feet
- Tics, tremors
Eye, Ear, Nose, Throat and Lungs
- Can't take a full breath which leads to low oxygen and this causes many other issues
- Swelling of the eyes or throat following exposure to a suspected allergen
- Mucus production
- Wheezing or difficulty breathing following exposure to an allergen or toxin
- Ears itch and/or are blocked, popping of the ears
- Ringing in the ears, especially after eating certain foods/drinks.
- Eyes may feel as if they have sand in them, burning sensation, dry, blurred vision and eyelid tics or spasms, swollen, red and itchy eyes, conjunctivitis
- Post nasal drip, nasal congestion, rhinitis (inflamed nose), sinusitis (inflamed sinuses)
- Pharyngitis, laryngitis, horseness, swollen throat
- Tongue swollen or sores in mouth, burning tongue or burning mouth, burning lips, sores on lips, itchy throat, trouble swallowing
- Fragrances bother the individual
- Dental issues - teeth deteriorating
Heart, and Blood Vessels - Cardiovascular
- Heart palpitations, rapid pulse, especially following a food like peanuts, dairy, wheat, corn, soy or other food
- Low blood pressure and passing out, light headed, dizzy,vertigo and fainting, palpitations, arrhythmias, chest pain, edema, postural orthostatic tachycardia syndrome, but can also cause hypertension
- Blood pressure swings around quite a bit
- Gastrointestinal inflammation causing symptoms such as swollen tongue, bloating, nausea, vomiting, diarrhea and cramp-like abdominal pain.
- Sudden abdominal bloating that makes the person look pregnant.
- Sudden diarrhea with or without alternating constipation
- Tingling or burning in the mouth or gut.
- Gastroesophageal reflux (GERD)
- Food sensitivities along with drug and chemical intolerances - worse with detox system genetic variants or overuse of detox system
- Dysbiosis or gut flora imbalance
- Compromised intestinal wall barrier - (Leaky gut)
- Interstitial cystitis
- Recurrent bladder infections
- Frequent urination
- Sensation of bladder infection
- Muscle pain that moves around
- Joint pain that moves around
Menstrual Related Issues
- PMS - really bad symptoms
- Menstrual cramps
- Pelvic pain
- Hot flushes
- Decreased libido
- Heavy periods
- Better when pregnant - many symptoms are gone due to high DAO in pregnancy
Other Common Symptoms
- Fatigue and general malaise (feeling ill or unwell)
- Feel inflamed or have many inflammatory illnesses
- Enlarged lymph nodes
- Excessive reactions to insect bites, iodine contrast dyes, local and general anesthetics.
- Migrating angio-edema (swelling) - fluid accumulation around eyes, lips, hands, feet.
- Inflammation in the bladder, vagina, prostate, pelvic pain
- Fibromyalgia type pain that moves around and is not easy to remedy
- Symptoms come and go and can't make sense of them
- Weight gain or loss
- Heat and cold intolerance
- Family history of cancer, especially intestinal or bone marrow
If the symptoms appear to be related to eating or drinking something and come on quickly afterwards, it may be a mast cell activation. Any symptoms developing within minutes after putting a substance in your mouth should make you ask if this is a mast cell reaction.
Implicated In A Variety of Diseases
- Allergy - hay fever, involved in some food allergies
- Autoimmune Disease such as rheumatoid arthritis and lupus
- Cancer - links to some types of cancer
- Cardiovascular disease
- CIRS - due to water-damaged buildings
- Connective Tissue Disease - may be link between Ehlers-Danlos syndrome and autonomic dysfunction (dysautonomia)
- Depression - Mast cells and brain inflammation related to depression
- Chronic Fatigue Syndrome
- Chronic Inflammatory Response Syndrome
- Gastrointestinal disorders such as GERD (reflux) and irritable bowel
- Many types of malignancies
- Multiple chemical sensitivity
- Multiple Sclerosis
- Postural orthostatic hypotension
- Skin conditions such as eczema and psoriasis
- Tinnitus - ringing of the ears
How Mast Cells Are Activated
The mast cell senses a threat and activates by producing chemicals that help the body address the threat. When it works properly all is well. However, if there are excess threats or the body reacts to something as a threat that is not a threat (allergens), or perhaps the mast cell acts overzealously, we can get an abnormal response and excess chemicals are released. This sets off an alarm that starts an inflammatory cascade that involves both the innate and adaptive immune system and a lot of inflammation. You may have seen someone react to a bee sting by swelling up and having trouble breathing, or an abnormal amount of inflammation from a mosquito bite. This is abnormal mast cell activation. This is not a usual response. The mast cells over-reacted. In an acute situation this can even be deadly.
- Masts cells can be activated by pathogens (virus, bacterial, parasites), medications, chemicals, foods, infections, heavy metals, and biotoxins such as venom or mycotoxins and other toxins in general.
- Mast cell activation has been shown to take place during intoxication from the mycotoxin T-2, and clinically it appears to me that other mycotoxins cause mast cell activation also. It would appear from research studies that mold and yeasts themselves also trigger mast cell activation.
- Mast cells have estrogen receptor sites and therefore can be stimulated by estrogen. It also decreases DAO levels. Progesterone naturally lowers histamine levels, so women who are estrogen dominant will have higher histamine levels.
- Emotional stress can trigger mast cells.
- Sometimes they go haywire and release mediators due to abnormal signals of the body.
- Sometimes there are mast cell mutations, and they overproduce, and spontaneoulsy release mediators. These abnormal cells can grow out of control, and are very sensitive to activation. This is a condition called mastocytosis.
- Sometimes mast cells are activated for no apparent reason. This is called idiopathic mast cell activation syndrome (MCAS).
- Mast cell activation, and degranulation involves the release of mediators such as histamine, serotonin, eicosanoids such as thromboxanes, leukotrienes and prostaglandins, as well as inflammatory cytokines like TNF-alpha, chemokines, and IL-4. Additionally, mast cells will store, and release ATP into the extracellular environment. The result is an inflammatory response that can have various systemic and localized effects.
- When there is an abundance of toxins or pathogens in the body and it overloads the body, this causes the mast cells to be overstimulated and hyperreactive. Now any stimulus, even tiny ones can cause mast cells to react and release their packets of chemicals, the main one being histamine. This kind of reaction is seen often in people with mold illness or the Lyme co-infection called Bartonella, but can also be from any type of over-burdeon of environmental toxins or pathogen toxins that are irritating and inflamming the body. We call this response "Mast Cell Activation Disorder".
Other Reasons for High Histamine
Although activation of mast cells is one way histamine is increased, histamine can also be incrased in the body due to other instigating factors.
- Genetic variants in the genes that express enzymes that degrade histamine can increase histamine due to lack of tranformation and removal.
- Histamine is also made by some gut bacteria, both commensal bacteria and pathogenic bacteria are included in this group.
- There is also food that is high in histamine. This includes fermented foods, spoiled food, salami, any meat that is old should be suspect.
- Anything that lowers DAO will increase histamine.
- Inflammatory or degerative bowel diseases are a cause of temporary DAO deficiency.
- Anything that disrupts the intestinal epithelium may lead to DAO deficiency as 90% of DAO is produced from intestinal epithelium.
- Some drugs will inhibit DAO.
- Genetic variant mentioned above.
So histamine comes from other areas than mast cells and mast cell activation is not necessary for chronic histmaine reactions.
Diagnosing Mast Cell Activation or High Histamine Issues
Mast cell activation can look like many different illnesses and although there are tests, these tests have limiting factors that keep them from being as useful as one would like. Often the way this ends up being diagnosed is by ruling out other possible illnesses until all that is left is mast cell activation.
Increases in serum mast cell trypatase
urinary levels of N-methylhistamine, 11B-Prostaglandin F2alpha and/or Leukotriene E4 are the tests used to diagnose MCAS.
Total serum mast cell tryptase should be drawn between 30 minutes and two hours after the start of an episode, with baseline level obtained many days later. The urine tests are performed on a 24 hour collection of urine that is started immediately.
The problem with testing for any of the chemicals released by mast cells is that they disappear extremely quickly and if you don't test while in the middle of an episode, your test will likely come up negative.
You can also test for IgE and to IgE receptors can be tested for (anti-IgE, IgG) to rule out autoantibody medicated mast cell activation.
Testing for the patients who are genetically negative for KIt-D816V to rule out the rare condition known as mastocytosis. Mastocytosis is something different than mast cell activation we are discussing here.
Also rule out genetic variants that can decrease the amount of DAO (diamine oxidase) available. The gene associated with DAO is AOC1. The DNA variants are 47 C>T (rs10156191), 995 C>T (rs1049742), 1990 C>G (rs1049793).
More abnormal biological markers includes MMP-9, C4a, TGF beta and VEGF.
What To Do If There is Mast Cell Actiation or High Histamine
The best thing to do if a person has a Mast cell activation disorder is to figure out what is triggering it. Look for the toxins from the environment or pathogens in the individual. Then remove the toxins/pathogens or remove the individual from the environment. This should stop the mast cell activation. In the mean time, while figuring this out and treating the issue, there are many things that can be done to make the person feel better. These same treatments can be used for high histamine due to other factors.
- If the person has a genetic variant that is associated with reduced activity of diamine oxidase I suggest using DAO replacement at meals. If they have dysbiosis and especially if testing shows bacteria that tend to be associated with increased levels of histamine, DAO replacement is a good idea. Additionally, use of gut flora that tend to be associated with low levels of histamine can be taken for support. A company called Seeking Health makes both of these products. The DAO replacement is called Histamine Block and the gut flora is called Probiota Histaminx. No, I am not associated with the company. If a person is an under methylator they will have issues with the other enzyme HNMT and should be sure to support methylation.
- Be careful about probiotics. Some of them will actually increase histamine. This is a reason that some people find they can't use probiotics and react to some fermented foods. They are using products that include gut flora that enhance histamine in the gut. The one I mentioned called Probiota Histaminx has only flora that are known to decrease histamine in the gut.
- Treat any infections
- Treat leaky gut and support a healthy digestive tract
- Remove sources of allergens
- Stabalize mast cell release - see ideas below
- You can limit histamine in your diet, but removing all histamine foods can be too much of a challage for people often. Many healthy foods have histamine in them. An indivdiual may need to do this short-term, but long-term you want to remove the causative factors and if there are genetic variants, you want to support the person with methylation, DAO, or as needed otherwise.
- Reduce causes of emotional and mental stress as much as possible as stress can also incrase histamine.
- Use stress reduction techniques.
- Stay away from chemicals and environmental toxins. This includes chemicals/perservatives/food colorings in your food.
- Keep away from insects that sting or bite as they will induce histamine too.
- Extreme temps of both hot and cold can cause a histamine release.
- There are medications that can block DAO or can incude histamine. Stay away from them. Even some antihistamines are thought to do this and watch out if you stop them as if you don't taper off, you can have a major rebound effect.
- Keep away from fragrances that bother you.
- Anesthetics may increase histamine, so be aware of this if you are having a surgery
Histamine And Foods
All foods considered to be high histamine should be suspect as they can add fuel to the fire going on in your body. You are reacting to histamine released by your immune system and high histamine foods will bother you if you run out of one or both enzymes that remove histamine (usually diamine oxidase or DAO which is extracellularly). Histamine can be metabolized in 2 ways: by oxidative deamination by DAO (former name: histaminase) or by ring methylation by histamine-N-methyltransferase (HNMT). DAO is released into the circulation and is concentrated in the small intestine where it neutralizes the histamine in food or histamine made by some gut bacteria from histidine in your food. HNMT breaks down histamine at an intracellular level. It is found in high levels in the liver, and kidney and is important at breaking down histamine in the nervous system. HNMT is also important in the airway, where it protects against histamine in these tissues, including the bronchial epithelium where it protects against histamine induced asthma. Most people make plenty of these enzymes to take care of the incoming histamine, however when mast cells are releasing a lot of histmine, there is not enough enzymes to deal with it. Besides running out of enzymes, they may not have enough of the necessary nutrients to make the enzymes that degrade the histamine, or they might have a decreased ability to make these enzymes for genetic reasons.
There are both foods high in histamine as well as foods that compete for the same enzymes needed to degrade histamine and foods that trigger mast cell release of histamine. All these categories will add to the histamine load and inflammation in the body for people who are sensitive. Foods high in histamines include alcohol (think red wine, beer), aged meats, spoiled meat, shellfish and fermented products. Then there is the fact that histamine is made from the amino acid histidine. A carboxyl group is removed from the amino acid histidine and it becomes histamine. Some bacteria and yeast can change histidine in foods to histamine, which is why fermented foods containing protein can be high in histamine. Some gut bacteria can turn histidine in foods into histamine also. Some gut flora will increase histamine levels in the gut while others will lower it. A product called Probiota Histaminx was made to specifically lower histamine in the gut and is useful to people with high histamine. If a person has dysbiosis (gut bacteria imbalance) they may end up making histamine from any high protein food containing histidine. Such foods are beef, bison, pork, parmesan cheese, pork, chicken, turkey, lamb, soy, fish such as tuna, catfish and to a lesser degree seeds, nuts and beans and even lesser degree, grains. Here is a list of foods high in histidine. Some cuts of meat are lower than others from the same animal.
There are also some foods that trigger histamine release from mast cells. These include fruits such as chocolate, nuts, shellfish, bananas, tomatoes, kiwi, lime, lemon, pineapple, papaya and plum. Additionally some additives such as MSG, sulfites, nitrites, benzoate and artificial food colorings can increase histamine reactions in the body.
It is really sad when a person has a high or borderline high histamine situation going on and they use bone broth and fermented foods to support gut health and suddenly they are much sicker than before. This is due to raising the histamine level.
This link is the best list of foods that contain histamine or cause release or histamine that I have found.
There are some drugs known to block HNMT.
If an individual is taking one of these drugs, they may be adding to the excess histamine level in their body.
• Chloroquine (Amodiaquin, an antimalarial))
• Folate antagonists such as metoprine (HNMT requires folate for activity)
• Tacrine (anticholinesterase, early Alzheimer’s drug)
Additional Support Making Enzymes
- Make sure the person has the nutrients for DAO, MAO and HNMT, as well as taking DAO with meals.
- DAO deficiency is associated with low B6 and copper deficiencies. Making sure these are adequate as necessary. Remember copper used long term needs to be taken with zinc in 1:8 (copper:zinc) proportion.
- Bifido bacteria (helpful probiotic that does not increase histamine - take after dinner and away from anti-microbials) - A variety of Bifidobacterium appear helpful including bifidobacterium infantis, longum, breve, bifidum and lactis. Additionally Lactobacillus plantarum and salvarius are also helpful.
- HNMT depends on methylation, so making sure there is adequate methylation support if needed is important. Two genetic variants that can affect methylation are MTHFR C677T rs1801133 and MTHFR A1298C rs1801131. There are also HNMT gene variants, but until more is known about them and ways to support the variants it does not make sense to pursue this.
Demulcent herbs to consider if there is an irritated gut from excess histamine
- Slippery elm
Also consider gut healing nutrients
- Vitamin A
- Alpha lipoic acid - Chronic use can interfere with biotin and it may need to be supplemented.
Help with gas and bloating
If there are pathogens found on testing, they must first be dealt with or no amount of healing activity will give persistent relief.
Support Stabalizing Mast Cells (Immune Support) and Antihistamine Activity
- Fish oil to stabilize cell membranes and decrease inflammation/histamine leakage from mast cells
- Vitamin C to also stabalize mast cells - small doses often through-out day or 30 minutes before meals.
- Quercetin - high doses are often helpful - up to 500 mg 4 times per day. Starting slowly moving up to this dose over a couple weeks. Some people may react to it and need super low doses (Neuroprotek LP - 40 mg) which will work for them. Take 30 minutes before meals and one before bed.
- Phosphatidylcholine to support cell wall membranes
- A study found mung bean sprouts (48 hours of sprout growth) provided significant protection against mast cell degranulation and histamine release due to their high flavonoid content. - 30 minutes before meals.
- There are many herbs that stabalize mast cells and keep histamine from being released.
- Creatine if methylation is not up to par as HNMT won’t work well with decreased methylation (most of your methylation activity goes to produce phosphatidylcholine and creatine, so supplementation helps decrease need for methylation if that is an issue for the individual)
- Methylation support - If there is impaired methylation due to MTHFR single nucleotide polymorphism consider support of methylation with b12, folate, B6 (as pyridoxal 5 phosphate), trimethylglycine, and riboflavin.
- Perimine (extract of Perilla seed) - One capsule 30 minutes before meals.
- AllQlear - Made from quail eggs. Contains a tryptase blocker - tyrptase is another mediator released from Mast cells. 1-2 tablets 30 minutes before meals.
- Turmeric - Curcuma longa
- Glutathione - antioxidant that helps to neutralize inflammatory mediatiors. If there is not enough, this will add to the inflammation as oxidative stress will result in mast cells releasing more chemicals and there will be more histamine. There will be further need for neutralizing the inflammatory mediators made by the mast cells and more need for glutathione. You can see an inflammatory ciricle is created here. Glutathione and other sulfur containing supplements and food can feed bacteria in the intestine that makes hydrogen sulfide and can lead to gut inflammation that can compromise the gut lining sometimes. If this happens you probably have an overgrowth of these bacteria and will want to decrease them. You will also need to back off on the sulfur containing supplements a bit perhaps.
- Gut bug support such as Lactobacillus rhamnosus and Bifidobacterium spp.
There are many herbs that stabalize mast cells and keep histamine from being released.
Polyphenols And Mast cell Stabilization
Foods high in a class of polyphenols called flavonoids are able to assist in decreasing mast cell activation and reduce histamine in the body. These flavonoids include quercetin and catechin which are found in herbs such as Green tea, Chamomile, Hawthorne and Gingko. Quercetin is found in many foods/herbs and some good choices for quercetin content are garlic, onions, capers, fruits with dark red or blue colors such as blueberries and cranberries. Elderberries are high in quercetin as well as Lovage and kale. Quercetin’s anti-inflammatory activity appears to be due to its antioxidant effects and inhibition of cyclooxygenase and lipoxygenase, which in turn regulate the inflammatory mediators leukotrienes and prostaglandins. Quercetin has been shown to stabilize mast cells, which inhibits release of histamine.
Research Studies Identified Herbal Constituents That Stabilize Mast Cells
- Epigallocatechin gallate found in Green tea – Camellia sinensis can inhibit the release of histamine from mast cells.
- Theanine is another constituents found in Green tea - Camellia sinensis. This amino acid has been shown to prevent histamine release from cells when in low concentrations.
- Ellagic acid found in fruits such as raspberries, strawberries, walnuts and pomegranate inhibit histamine release as well as proinflammatory cytokines such as TNF-alpha and Il-6.
- Khellin from the herb Khella – Ammi visnaga has been shown to stabilize mast cells. This is also an herb that is used to prevent Asthma attacks. I have found it especially useful in the past for exercise induced asthma. Khella is not an herb that is used for immediate relief, and high doses may cause side effects such as liver damage.)
- Silibinin from the herb Milk thistle- Silybum marianum prevents histamine release as well as preventing release of other inflammatory cytokines from mast cells.
- Reservatrol found in the herb Japanese knoteweed - Polygonum cuspidatum, as well as the foods grapes, peanuts, and blueberries, was found to suppress inflammatory cytokines linked to mast cell disorders, specifically tumor necrosis factor and interleukins.
- Curcumin from the herb Turmeric – Curcuma longa prevents release of histamine by stabilizing mast cells and inhibits cytokines IL-4 and TNF-alpha.
- Parthenolide from the herb Feverfew – Tanacetum parthenium stabalizeds mast cells.
- Indoline from the herb Woad - Isatis tinctoria stabilized mast cells.
- Estragole from the herb Basil - Ocimum basilicum reduces inflammation due to edema and arachidonic acid.
Additional foods/herbs that might be useful to stabilize mast cells or decrease histamine release
- Pea sprouts
- Black cumin
I can't end this article without mentioning mastocytosis. This is different than mast cell activation or high histamine for other reasons.
Mastocytosis is all about mast cell proliferation. There is inappropriate mast cell activation, where the mast cells release their contents more easily than normal. Additionally, there are excess numbers of mast cells being made by the body. There are two main types.
- Cutaneous - limited to the skin only
- Systemic - spread throughout the body
Read more about mastocytosis.
Remember To Send This To Friends And Family Who Will Benefit From Reading It!